Epidemiologic and animal studies have established that natural dietary components and supplements reduce cancer risk. Colorectal carcinoma (CRC) is the second most common cause of death from malignant disease in the US; the mortality rate is ~50%. Diseases associated with long-term inflammation of the colon, such as chronic ulcerative colitis (UC) and Crohn's disease (CD), increase the risk for CRC. Patients with chronic inflammatory disease have limited options to reduce this risk. Dietary constituents can be developed for chemoprevention, especially since most are tolerated at high doses without serious side-effects. An inverse correlation exists between serum levels of 1, 25-dihydroxyvitamin D (1,25D) and CRC incidence. 1,25D functions by binding to the vitamin D receptor (VDR). In conditions of chronic inflammation, cytokine release increases expression of the transcription factors Snail1 and Snail2/Slug, leading to suppressed VDR levels and failure to respond to 1,25D. The flavonolignan silibinin, isolated from milk thistle seeds, suppresses Snail1 and Slug levels. We propose that Snail1/Slug-mediated decrease in VDR levels in chronic inflammation, accounting for failure to respond to 1,25D, can be reversed by co-treating with silibinin, restoring the beneficial effects of 1,25D and leading to a favorable prognosis. In support, we show that, in HT-29 human colon cells, tumor necrosis factor- (TNF-) increases Snail1 and Slug levels, decreases VDR levels, and suppress 1,25D's anti-proliferative effects. Silibinin decreases Snail1 and Slug levels, increases VDR levels, reverses the TNF- effects on Snail1, Slug and VDR and on cell proliferation, and restores Vitamin D Response Element-mediated promoter activity in 1,25D-unresponsive cells. Silibinin and 1,25D synergistically inhibit TNF--induced cell proliferation. Our long-term goal is to determine if silibinin and 1,25D analogs function synergistically as chemopreventive agents to prevent CRC development in conditions of chronic inflammation. We will test our hypothesis by pursuing these Specific Aims. 1) The role of 1,25D signaling in the silibinin-mediated protective effects against inflammatory cytokine-mediated colon cell damage will be assessed using cell proliferation, migration and invasion as readouts; and 2) the effect of a silibinin + EB1089 (non-hypercalcemic 1,25D analog) regimen on inflammation and tumorigenesis will be evaluated in the AOM/DSS (azoxymethane/dextran sodium sulfate) mouse model. These studies will lay the foundation for future mechanistic and translational studies aimed at developing a 1,25D analogs + silibinin regimen to prevent CRC in patients with chronic inflammation.